Epithelia such as the epidermis of the skin are characterized by stereotyped differentiation programs where populations of stem cells are maintained in a careful equilibrium between proliferation and tissue-specific differentiation. Interruption of this balance significantly impairs the function of the skin and results in variety f disease states. Many skin diseases such as epidermolytic hyperkeratosis (EH), psoriasis and ichthyosis are associated with abnormal differentiation.1,2,3 Changes in differentiation are also seen in squamous cell carcinoma (SCC) of the skin, and conversely, many disorders in which the skin barrier is compromised (e.g. EH) lead to excessive proliferation, increasing SCC susceptibility. Though most prevalent in the skin, SCCs occur in many other stratified squamous epithelial tissues such as those of lung, head, neck, breast and vagina. Often, the degree of differentiation of these tumors is a predictor of patient prognosis. 4,5,6 A deeper understanding of how differentiation is established during development and maintained during tissue homeostasis provides insight into the pathogenesis of a variety of skin disease causing significant morbidity. Anaplasia, or the undifferentiated appearance of a tumor, has been a well characterized observation of clinicians for over a century. Despite this correlation the role that changes in differentiation play in progression of malignancies, particularly of solid tumors, is no clear. In the skin the differentiation program is established during a stereotyped developmental period where a single layer of cuboidal cells transforms into a complex layered epithelium essential for life. My study focuses on elucidating the changes that naturally occur during epidermal development in order to understand how changes associated with skin diseases such as SCC affect the differentiation program. This work will clarify what role perturbations in these changes play in disease progression. The answers should illuminate whether methods to restore the proper differentiation program might present a new avenue to combat development of squamous cell carcinoma (SCC). I aim first to elucidate the complex transcriptional profiles associated with epidermal stem cells as they stratify, differentiate and form mature skin tissue with a barrier to keep microbes out and retain body fluids. Next I will investigate how the gene expression changes that are known to be associated with SCC malignancy affect this differentiation program. Finally I aim to understand how the differentiation changes associated with squamous cell carcinoma affect tumor initiation and progression.